Changes In Skeletal Muscle Metabolism Research Articles

Mediators of cachexia in cancer patients.

Alterations in amino acid and protein metabolism-particularly in skeletal muscle-are a key feature of cancer that contributes to the cachexia syndrome. Thus, skeletal muscle protein turnover is characterized by an exacerbated rate of protein degradation, promoted by an activation of different proteolytic systems that include the ubiquitin-proteasome and the autophagic-lysosomal pathways. These changes are promoted by both hormonal alterations and inflammatory mediators released as a result of the systemic inflammatory response induced by the tumor. Other events, such as alterations in the rate of myogenesis/apoptosis and decreased regeneration potential also affect skeletal muscle in patients with cancer. Mitochondrial dysfunction also contributes to changes in skeletal muscle metabolism and further contributes to the exacerbation of the cancer-wasting syndrome. Different inflammatory mediators-either released by the tumor or by the patient's healthy cells-are responsible for the activation of these catabolic processes that take place in skeletal muscle and in other tissues/organs, such as liver or adipose tissues. Indeed, white adipose tissue is also subject to extensive wasting and "browning" of some of the white adipocytes into beige cells; therefore increasing the energetic inefficiency of the patient with cancer. Recently, an interest in the role of micromRNAs-either free or transported into exosomes-has been related to the events that take place in white adipose tissue during cancer cachexia.

Abstracts of the 11th International Conference on Cachexia, Sarcopenia and Muscle Wasting, Maastricht, The Netherlands, 7–9 December 2018 (Part 2)

Abstracts of the 11^th International Conference on Cachexia, Sarcopenia and Muscle Wasting, Maastricht, The Netherlands, 7–9 December 2018 (Part 2)

Exacerbated metabolic changes in skeletal muscle of sickle cell mice submitted to an acute ischemia-reperfusion paradigm.

Sickle cell disease (SCD) is characterized by painful vaso-occlusive crisis. While there are several metabolic abnormalities potentially associated with muscular ischemia-reperfusion cycles that could be harmful in the context of SCD, the metabolic consequences of such events are still unknown. Ten controls (HbAA), thirteen heterozygous (HbAS), and ten homozygous (HbSS) SCD mice were submitted to a standardized protocol of rest-ischemia-reperfusion of the left leg during which adenosine triphosphate, phosphocreatine, and inorganic phosphate concentrations as well as intramuscular pH were measured using phosphorous magnetic resonance spectroscopy (MRS). Forty-eight hours later, skeletal muscles were harvested. Oxidative stress markers were then measured on the tibialis anterior. At the end of the ischemic period, HbSS mice had a lower pH value as compared with the HbAA and HbAS groups (P<0.01). During the reperfusion period, the initial rate of phosphocreatine resynthesis was lower in HbSS mice as compared with HbAA (P<0.05) and HbAS (P<0.01) animals. No significant difference among groups was observed regarding oxidative stress markers. HbSS mice displayed a higher intramuscular acidosis during the ischemic period while their mitochondrial function was impaired as compared with their HbAA and HbAS counterparts. These metabolic abnormalities could worsen the complications related to the pathology of SCD.

Epigenetic and Metabolic Changes in Skeletal Muscle Underlying the Improvement of Insulin Sensitivity after Bariatric Surgery in Humans

Weight loss-induced improvement in insulin sensitivity (IS) has been related to enhanced muscle energy metabolism. Thus, we hypothesized that weight loss due to bariatric surgery may induce epigenomic changes, which in turn modify mitochondrial function and intracellular lipids. We previously reported that IS fails to improve at 2 weeks (2 w), but then continuously increases until 52 weeks (52 w) after surgery. Now, we monitored muscle mitochondrial function and lipid intermediates in 49 obese humans (OBE; 40±10 years, BMI 51±7 kg/m2) before and for 52 w after bariatric surgery. Genome-wide gene expression and DNA methylation were analyzed in a subgroup of 16 OBE. Initial weight loss increases muscle oxidative capacity by 11% at 2 w, but transient elevation of certain muscle diacylglycerols resulting from unrestrained adipose lipolysis prevents from rapid improvement in IS. At 52 w, both mitochondrial function and intracellular lipids are comparable to lean humans. Acute alterations in expression of 1287 genes involved primarily in mitochondrial function, transcriptional regulation, protein transport, fatty acid metabolism and inflammatory processes, but not changes in DNA methylation, underlie the transient upregulation of mitochondrial function and lipolysis. At 52 w, 1091CpGs are differentially methylated, which relates to improved IS. Specifically, epigenetic alterations at 52 w in FTO gene, encoding an α-ketoglutarate dependent dioxygenase, and TOMM7 gene, encoding a translocase of the outer mitochondrial membrane, contribute to reprogramming transient changes in mRNA expression at 2 w. In conclusion, initial metabolic changes after weight loss induce epigenetic modification of genes involved in muscle energy metabolism, which in turn leads to long-term beneficial changes in gene expression. Disclosure S. Gancheva: None. M. Ouni: None. C. Koliaki: None. T. Jelenik: None. D.F. Markgraf: None. J. Szendroedi: None. M. Schlensak: None. A. Schuermann: None. M. Roden: Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Poxel SA. Research Support; Self; Danone Nutricia Early Life Nutrition, GlaxoSmithKline plc., Nutricia Advanced Medical Nutrition, Sanofi.

Investigating Muscle Function After Stroke Rehabilitation with 31P-MRS: A Preliminary Study

BackgroundNew evidence reveals significant metabolic changes in skeletal muscle after stroke. However, it is unknown if 31P magnetic resonance spectroscopy (31P-MRS) can evaluate these metabolic changes. Our objective here was to investigate: (a) if muscle energy metabolism changes in the affected side; (b) if muscle energy metabolism changes after rehabilitation; and (c) if energy metabolism measured by 31P-MRS can reflect changes in the Modified Modified Ashworth Scale (MMAS) and Fugl-Meyer assessment-lower extremity (FMA-LE) scores after rehabilitation.Material/MethodsWe enrolled 13 patients with stroke symptoms and hemiplegia. Lower-limb motor status on the affected side was evaluated by FMA-LE and MMAS. The 31P-MRS measures included phosphocreatine (PCr), inorganic phosphate (Pi), PCr/Pi, and pH. We statistically compared these measures in the affected and unaffected lower leg muscles before rehabilitation and after rehabilitation on the affected side. Spearman correlational analyses was performed to determine correlations between change in energy metabolism and change in FMA-LE score and MMAS score after rehabilitation.ResultsPCr and PCr/Pi were significantly lower in the affected muscle compared to the unaffected muscle; however, there were no significant differences in Pi or pH. After rehabilitation, PCr, Pi, PCr/Pi, and pH did not significantly change. However, FMA-LE and MMAS score improved significantly after rehabilitation. Changes in energy metabolism measured by 31P-MRS had no correlation with FMA-LE change after rehabilitation. However, changes in PCr and PCr/Pi were correlated with change in MMAS score after rehabilitation.Conclusions31P-MRS can evaluate changes in muscle energy metabolism in patients with stroke. PCr measured by 31P-MRS can reflect changes in MMAS after rehabilitation.

Exercise Training in Standardbred Horses Alters the Skeletal Muscle Metabolome and Plasma Amino Acid Profile: Implications for the “Athlete's Paradox”

To date equine skeletal muscle metabolism has centered on a limited number of candidate metabolites. As such, there is a dearth of information regarding global changes in skeletal muscle metabolism following exercise training. Thus, the purpose of this study was to determine the effects of exercise training on skeletal muscle metabolism through changes in the skeletal muscle metabolome in healthy, untrained Standardbred horses. In addition, we aimed to determine the extent to which protein metabolism is also altered through changes in the concentrations of plasma amino acids (AA). We hypothesized that training would significantly alter the skeletal muscle metabolome, as well as protein metabolism, as reflected in changes in the plasma AA profile. Eight untrained, Standardbred horses (n=4 mares, n=4 geldings; 3–9 yrs; 485 ± 13 kg, mean ± S.E.) underwent a 12‐week training program that significantly increased VO2 and exercise capacity (p&lt;0.05). Percutaneous needle biopsies were obtained from the M. gluteus medius in the untrained state (UT) and again following training (TR). Frozen muscle samples were submitted to Metabolon, Inc. for global metabolite profiling via UHPLC‐MS/MS. Blood obtained via jugular venipuncture was placed into EDTA tubes for the measurement of plasma AA concentrations via HPLC. For metabolomics analysis, differences between UT and TR samples were evaluated by two way‐ANOVA and Welch's t‐test for paired comparisons and considered significant at p&lt;0.05. For plasma AAs, differences were analyzed via Student's t‐test and considered significant at p&lt;0.05. Training resulted in significant alterations in lipid, branched‐chain amino acid (BCAA), and nucleotide metabolite classes in skeletal muscle. Of note, analysis revealed significant increases in the relative abundance of almost every identified FFA and complex lipid species in TR compared to UT muscle (p&lt;0.05), particularly the long‐chain (LC)‐acylcarnitines and diacylglycerides (DAGs) (1.5 to 2.3‐fold increases). Further, TR muscle exhibited increased fold‐changes (1.2 to 4.2‐fold) of C4 and several C5 BCAA‐derived acylcarnitines compared to UT (p&lt;0.05). In plasma, training caused a significant 36% increase in the concentration of total essential AAs (p&lt;0.05), of which and interestingly there was a significant increase in total BCAAs (42%, p&lt;0.05) and phenylalanine (27%, p&lt;0.05). In conclusion, exercise training significantly increased blood concentrations of total EAAs and BCAAs alongside significant increases in the relative abundances of certain skeletal muscle metabolites (i.e. LC‐acylcarnitines, BCAA‐derived acylcarnitines, and DAGs) that have been shown to be elevated during obesity and are proposed to play a role in the development of insulin resistance. These data underscore the complex nature of static metabolic signatures and the role that certain metabolites play in mediating health and disease. Future research should aim to utilize other sophisticated techniques that can address issues of metabolite flux and tissue utilization.Support or Funding InformationThis research was supported by: the New Jersey Institute for Food, Nutrition and Health (IFNH), USDA NIFA (NC 1184), the Rutgers University Equine Science Center (ESC), and the New Jersey Agriculture Experiment Station (NJAES).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The Nuclear Receptor Nor-1 Is a Pleiotropic Regulator of Exercise-Induced Adaptations.

Exercise induces various physical and metabolic changes in skeletal muscle that adaptively reprograms this tissue to current physiological and environmental demands. Underlying these changes are broad modifications to gene expression. We postulate that the nuclear hormone receptor, Nor-1, is activated after exercise, and this transcription factor modifies gene expression to drive the molecular and cellular adaptations associated with contractile reorganization.

Dietary Fat Quantity and Type Induce Transcriptome-Wide Effects on Alternative Splicing of Pre-mRNA in Rat Skeletal Muscle

Background: Fat-enriched diets produce metabolic changes in skeletal muscle, which in turn can mediate changes in gene regulation.Objective: We examined the high-fat-diet-induced changes in skeletal muscle gene expression by characterizing variations in pre-mRNA alternative splicing.Methods: Affymetrix Exon Array analysis was performed on the transcriptome of the gastrocnemius/plantaris complex of male obesity-prone Sprague-Dawley rats fed a 10% or 60% fat (lard) diet for 2 or 8 wk. The validation of exon array results was focused on troponin T (Tnnt3). Tnnt3 splice form analyses were extended in studies of rats fed 10% or 30% fat diets across 1- to 8-wk treatment periods and rats fed 10% or 45% fat diets with fat sources from lard or mono- or polyunsaturated fats for 2 wk. Nuclear magnetic resonance (NMR) was used to measure body composition.Results: Consumption of a 60% fat diet for 2 or 8 wk resulted in alternative splicing of 668 and 726 pre-mRNAs, respectively, compared with rats fed a 10% fat diet. Tnnt3 transcripts were alternatively spliced in rats fed a 60% fat diet for either 2 or 8 wk. The high-fat-diet-induced changes in Tnnt3 alternative splicing were observed in rats fed a 30% fat diet across 1- to 8-wk treatment periods. Moreover, this effect depended on fat type, because Tnnt3 alternative splicing occurred in response to 45% fat diets enriched with lard but not in response to diets enriched with mono- or polyunsaturated fatty acids. Fat mass (a proxy for obesity as measured by NMR) did not differ between groups in any study.Conclusions: Rat skeletal muscle responds to overconsumption of dietary fat by modifying gene expression through pre-mRNA alternative splicing. Variations in Tnnt3 alternative splicing occur independently of obesity and are dependent on dietary fat quantity and suggest a role for saturated fatty acids in the high-fat-diet-induced modifications in Tnnt3 alternative splicing.

Flavan 3-ol delays the progression of disuse atrophy induced by hindlimb suspension in mice

Periods of skeletal muscle disuse, for example due to a sedentary lifestyle or bed rest, are associated with aging and can lead to muscle atrophy. We previously found that the flavan 3-ol fraction derived from cocoa (FL) enhanced energy expenditure with metabolic changes in skeletal muscle. In the present study, we examined the effect of FL on disuse muscle atrophy induced by hindlimb suspension in mice. Male C57BL/6J mice were assigned to four groups as follows: unsuspended-vehicle, unsuspended-FL, suspended-vehicle, and suspended-FL. Mice in the vehicle treatment groups were administered distilled water and those in the FL treatment groups were dosed with FL (50mg/kg/day) for 2weeks. The weights of the gastrocnemius (GC), tibialis anterior (TA), and soleus (SOL), but not the extensor digitorum longus (EDL), decreased significantly in mice with hindlimb suspension (−11.8%, −16.5%, and −41.0%, respectively). This reduction in GC, TA, and SOL mass was inhibited by FL (−5.3%, +2.0%, and −16.6%, respectively). The FL increased the EDL weight >20% with or without hindlimb suspension. The protein level of the ubiquitin ligase, muscle ring finger-1, in the SOL was significantly increased by hindlimb suspension, but inhibited by treatment with FL. Protein expression of p70S6 kinase in the SOL was significantly decreased by hindlimb suspension, and FL treatment inhibited this change. These results suggested that FL delayed disuse muscle atrophy by metabolic alteration.

The role of skeletal muscle contractile duration throughout the whole day: reducing sedentary time and promoting universal physical activity in all people.

A shared goal of many researchers has been to discover how to improve health and prevent disease, through safely replacing a large amount of daily sedentary time with physical activity in everyone, regardless of age and current health status. This involves contrasting how different muscle contractile activity patterns regulate the underlying molecular and physiological responses impacting health‐related processes. It also requires an equal attention to behavioural feasibility studies in extremely unfit and sedentary people. A sound scientific principle is that the body is constantly sensing and responding to changes in skeletal muscle metabolism induced by contractile activity. Because of that, the rapid time course of health‐related responses to physical inactivity/activity patterns are caused in large part directly because of the variable amounts of muscle inactivity/activity throughout the day. However, traditional modes and doses of exercise fall far short of replacing most of the sedentary time in the modern lifestyle, because both the weekly frequency and the weekly duration of exercise time are an order of magnitude less than those for people sitting inactive. This can explain why high amounts of sedentary time produce distinct metabolic and cardiovascular responses through inactivity physiology that are not sufficiently prevented by low doses of exercise. For these reasons, we hypothesize that maintaining a high metabolic rate over the majority of the day, through safe and sustainable types of muscular activity, will be the optimal way to create a healthy active lifestyle over the whole lifespan.

Principles, insights, and potential pitfalls of the noninvasive determination of muscle oxidative capacity by near-infrared spectroscopy.

Skeletal muscle oxidative capacity is highly plastic, strongly associated with whole-body aerobic capacity (16, 18) and state of health. Loss of muscle oxidative capacity is associated with physical inactivity, aging and chronic disease (17), and has been implicated in the pathophysiology of obesity and diabetes (21). Evaluating these changes has traditionally been limited to invasive or costly assessments (biopsy or ³¹P MRS). To address this, Hamaoka and colleagues developed an innovative, non-invasive approach using near-infrared spectroscopy (NIRS) to quantitatively measure muscle oxygen consumption (mVO₂; 12) and use this to infer muscle oxidative capacity based on the mVO₂ recovery rate constant (k) (23; later modified 26). This technique has been subsequently used to interpret relative differences in oxidative capacity across a wide range of muscles, ages and disease states (Figure 1C). The purpose of this Viewpoint is to open a discussion on the principles, insights and potential pitfalls of using NIRS to measure k and infer muscle oxidative capacity.

Regional Variation in Skeletal Muscle and Adipose Tissue FDG Uptake Using PET/CT and Their Relation to BMI

Skeletal muscle metabolism is a primary contributor to whole-body energy expenditure. Currently, methods to measure changes in skeletal muscle metabolism in vivo are limited. Our objectives were to characterize the regional variation in skeletal muscle and adipose tissue (AT) FDG uptake as a surrogate for glycolytic metabolism using 18F-2-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) in healthy men and to correlate these findings to body mass index (BMI). Eighteen healthy men were enrolled and underwent FDG-PET/CT. The mean standardized uptake value of 14 skeletal muscles and two AT regions was measured and linear regression analysis was performed to identify metabolic predictors of BMI. FDG-PET/CT reliably detected changes in skeletal muscle and AT depot metabolic activity based on location. The most metabolically active muscles were those used for posture and breathing, which have the highest percentage of reported type I muscle myofiber content. Visceral AT tended to have a higher FDG uptake than subcutaneous AT. The mean standardized uptake value of VAT, pectoralis major, and gluteus maximus muscles accounted for 64% of the variance in BMI. FDG-PET/CT can be used to quantify the regional variation in glucose metabolism of multiple skeletal muscle groups and AT depots.

Tumor Necrosis Factor-α Promotes Phosphoinositide 3-Kinase Enhancer A and AMP-Activated Protein Kinase Interaction to Suppress Lipid Oxidation in Skeletal Muscle.

Tumor necrosis factor-α (TNF-α) is an inflammatory cytokine that plays a central role in obesity-induced insulin resistance. It also controls cellular lipid metabolism, but the underlining mechanism is poorly understood. We report in this study that phosphoinositide 3-kinase enhancer A (PIKE-A) is a novel effector of TNF-α to facilitate its metabolic modulation in the skeletal muscle. Depletion of PIKE-A in C2C12 myotubes diminished the inhibitory activities of TNF-α on mitochondrial respiration and lipid oxidation, whereas PIKE-A overexpression exacerbated these cellular responses. We also found that TNF-α promoted the interaction between PIKE-A and AMP-activated protein kinase (AMPK) to suppress its kinase activity in vitro and in vivo. As a result, animals with PIKE ablation in the skeletal muscle per se display an upregulation of AMPK phosphorylation and a higher preference to use lipid as the energy production substrate under high-fat diet feeding, which mitigates the development of diet-induced hyperlipidemia, ectopic lipid accumulation, and muscle insulin resistance. Hence, our data reveal PIKE-A as a new signaling factor that is important for TNF-α-initiated metabolic changes in skeletal muscle.

Energy substrate levels and metabolic changes in skeletal muscle underlie increased activity and improved exercise performance in liver fatty acid‐binding protein null mice

Liver fatty acid‐binding protein (LFABP, FABP1) binds long chain fatty acids with high affinity, and is abundantly expressed in the liver and small intestine. Although LFABP is thought to function in intracellular lipid trafficking, studies of LFABP null (LFABP−/−) mice have also demonstrated a role in regulation of systemic energy homeostasis. We and others have reported that LFABP−/− mice become more obese than wild‐type (WT) mice upon high fat feeding. Despite increased body weight and fat mass, however, and in marked contrast to the drastic decrease in exercise capacity in high fat‐fed WT mice, LFABP−/− mice were able to maintain their endurance exercise performance, showing an approximate doubling of running distance compared with the WT mice. Therefore, to understand this surprising exercise phenotype, in the present studies we focused on the metabolic alterations in the skeletal muscle secondary to LFABP ablation. The results indicate significantly increased triglyceride (TG) content and glycogen content in the skeletal muscle of LFABP−/− mice. In addition, higher mitochondrial enzyme activities, in both the tricarboxylic acid (TCA) cycle and the electron transport chain, suggest that LFABP−/− muscle has greater energy substrate availability and greater capacity for substrate oxidation compared with WT muscle. Moreover, consistent with the findings that their muscle Pgc1α and Pparα mRNA levels were upregulated, LFABP−/−mice had an increased fatty acid oxidation rate in the skeletal muscle compared with WT mice. Interestingly, however, substrate utilization during exercise showed no differences between LFABP−/− and WT mice, as examined by respiratory exchange ratio, exercise‐dependent decreases in muscle TG and glycogen stores, and 5′AMP‐activated protein kinase activation levels. Thus, the LFABP−/− and WT mice appear to have similar energy production during exercise, indicating that the markedly improved exercise capacity in the LFABP−/− mice is related to their higher muscle substrate levels prior to exercise. Overall, the results show that although it is not expressed in muscle, LFABP ablation in the liver and intestine is associated with alterations in skeletal muscle energy metabolism and energy substrate levels. These changes may be due, in part, to liver‐and/or intestine‐derived mediators that contribute to the greater TG and glycogen availability and increased mitochondrial function, thereby preventing the high fat feeding‐induced decrease in exercise capacity.Support or Funding InformationThis work was supported by National Institutes of Health Grant DK‐38389 from NIDDK, and by funds from the New Jersey Agricultural Experiment Station (to J. S.).

Understanding Age-Related Changes in Skeletal Muscle Metabolism: Differences Between Females and Males.

Skeletal muscle is the largest metabolic organ system in the human body. As such, metabolic dysfunction occurring in skeletal muscle impacts whole-body nutrient homeostasis. Macronutrient metabolism changes within the skeletal muscle with aging, and these changes are associated in part with age-related skeletal muscle remodeling. Moreover, age-related changes in skeletal muscle metabolism are affected differentially between males and females and are likely driven by changes in sex hormones. Intrinsic and extrinsic factors impact observed age-related changes and sex-related differences in skeletal muscle metabolism. Despite some support for sex-specific differences in skeletal muscle metabolism with aging, more research is necessary to identify underlying differences in mechanisms. Understanding sex-specific aging skeletal muscle will assist with the development of therapies to attenuate adverse metabolic and functional outcomes.

The 2015 ESPEN Sir David Cuthbertson lecture: Inflammation as the driving force of muscle wasting in cancer

Alterations in amino acid protein metabolism are a key feature of the cancer cachexia syndrome. These changes -induced by both hormonal changes (that affect insulin sensitivity) and inflammatory mediators- are present in skeletal muscle influencing both, amino acid uptake and protein synthesis. In addition, skeletal muscle protein turnover is characterized by an exacerbated rate of protein degradation, promoted by an activation of different proteolytic systems that include the ubiquitin-proteasome and the autophagic-lysosomal pathways. Changes in the rate of myogenesis/apoptosis also determine skeletal muscle mass during cancer cachexia. Indeed, a decreased skeletal muscle regeneration capacity is observed together with an increased rate of cell death, resulting in muscle wasting. Mitochondrial dysfunction also results in changes in skeletal muscle metabolism and further contributes to the exacerbation of the cancer-wasting syndrome. Different inflammatory mediators -either released by the tumor or by healthy cells of the cancer patient- are responsible for the activation of these catabolic processes that take place in skeletal muscle.

Relationship between Maximum Oxygen Consumption and Muscle Oxygenation During a Cross Country Season

The purpose of this study was to examine the relationship between maximum oxygen consumption and muscle tissue oxygenation of collegiate cross country runners throughout their season. Seven collegiate cross country runners (six female and one male, 18.8±0.9 yrs) were studied early season (T1), mid season (T2), directly after their last meet (T3), and one week after their season was completed (T4). Each subject completed a graded exercise test to exhaustion on a motor driven treadmill. Subjects began running at seven mile per hour for two minutes. The elevation of the treadmill was gradually increased to volitional fatigue. A Parvo Medics TrueOne 2400 metabolic measurement system was used to determine oxygen consumption, expired ventilation, and respiratory exchange ratio at each exercise level and at maximum. Maximum oxygen consumption (VO2max) was then determined. Near‐infrared spectroscopy (Portamon, Artinis Inc.) was used to measure oxygenated hemoglobin, deoxygenated hemoglobin, total hemoglobin, and tissue saturation index (TSI) for each stage of the graded exercise test. The Portamon was placed over the vastus lateralis and secured. TSI is used as an index of muscle tissue oxygenation. In this study, the slope of the decline in TSI was determined and used to quantify the muscle oxygenation response. TSI data was smoothed via a moving average filter width of 5 seconds. The moving average filter calculates the unweighted mean of the measured data over the filter width. Overall, the TSI deceased at a slower rate during mid season (T2) compared to the early season (T1) testing (Slope: T1=−0.091±0.016; T2=−0.021±0.007). Furthermore, VO2 Max increased between T1 to T2 (VO2 Max: T1=58.5±9.1 ml//kg/min; T2=62.35±12.03 ml/kg/min). Muscle oxygenation declined at the fastest rate during the early part of the cross‐country season relative to mid‐season. At the same time, VO2max significantly increased between those two time points. Taken together, this suggests that adaptive changes as result of cross country training enables runners to be more efficient at utilizing oxygen probably as a result of adaptive metabolic changes in skeletal muscle.

Protective effect of myostatin gene deletion on aging-related muscle metabolic decline

While myostatin gene deletion is a promising therapy to fight muscle loss during aging, this approach induces also skeletal muscle metabolic changes such as mitochondrial deficits, redox alteration and increased fatigability. In the present study, we evaluated the effects of aging on these features in aged wild-type (WT) and mstn knockout (KO) mice. Moreover, to determine whether an enriched-antioxidant diet may be useful to prevent age-related disorders, we orally administered to the two genotypes a melon concentrate rich in superoxide dismutase for 12weeks. We reported that mitochondrial functional abnormalities persisted (decreased state 3 and 4 of respiration; p<0.05) in skeletal muscle from aged KO mice; however, differences with WT mice were attenuated at old age in line with reduced difference on running endurance between the two genotypes. Interestingly, we showed an increase in glutathione levels, associated with lower lipid peroxidation levels in KO muscle. Enriched antioxidant diet reduced the aging-related negative effects on maximal aerobic velocity and running limit time (p<0.05) in both groups, with systemic adaptations on body weight. The redox status and the hypertrophic phenotype appeared to be beneficial to KO mice, mitigating the effect of aging on the skeletal muscle metabolic remodeling.

Tumor necrosis factor-α impairs adiponectin signalling, mitochondrial biogenesis, and myogenesis in primary human myotubes cultures.

Skeletal muscle metabolic changes are common in patients with chronic heart failure (HF). Previously, we demonstrated a functional skeletal muscle adiponectin resistance in HF patients with reduced left ventricular ejection fraction (HFrEF). We aimed to examine the impact of adiponectin receptor 1 (AdipoR1) deficiency and TNF-α treatment on adiponectin signaling, proliferative capacity, myogenic differentiation, and mitochondrial biogenesis in primary human skeletal muscle cells. Primary cultures of myoblasts and myotubes were initiated from the musculus vastus lateralis of 10 HFrEF patients (left ventricular ejection fraction; 31.30 ± 2.89%) and 10 age- and gender-matched healthy controls. Healthy control cultures were transfected with siAdipoR1 and/or exposed to TNF-α (10 ng/ml; 72 h). Primary cultures from HFrEF patients preserved the features of adiponectin resistance in vivo. AdipoR1 mRNA was negatively correlated with time to reach maximal cell index (r = -0.7319, P = 0.003). SiRNA-mediated AdipoR1 silencing reduced pAMPK (P < 0.01), AMPK activation (P = 0.046), and myoblast proliferation rate (xCELLigence Real-Time Cellular Analysis; P < 0.0001). Moreover, TNF-α decreased the mRNA expression of genes involved in glucose (APPL1, P = 0.0002; AMPK, P = 0.021), lipid (PPARα, P = 0.025; ACADM, P = 0.003), and mitochondrial (FOXO3, P = 0.018) metabolism, impaired myogenesis (MyoD1, P = 0.053; myogenin, P = 0.048) and polarized cytokine secretion toward a growth-promoting phenotype (IL-10, IL-1β, IFN-γ, P < 0.05 for all; Meso Scale Discovery Technology). Major features of adiponectin resistance are retained in primary cultures from the skeletal muscle of HFrEF patients. In addition, our results suggest that an increased inflammatory constitution contributes to adiponectin resistance and confers alterations in skeletal muscle differentiation, growth, and function.

Effect Of Exercise On Interstitial PO2 And Contractile Function In The Diaphragm Of Diabetic Rats

Type I diabetes in rats causes structural, functional, and metabolic changes in skeletal muscle which impair contractile function and alter the balance between oxygen delivery (QO2) and oxygen consumption (VO2), as reflected by changes in interstitial PO2 (PiO2). Exercise improves the QO2 to VO2 balance and muscle function. The diaphragm is also affected by diabetes however the impact of exercise training on QO2 to VO2 balance and contractile function in diabetic rats is not well described. PURPOSE: To determine the effect of low intensity exercise training on PiO2 at the onset of contractions compared to sedentary diabetic rats, and to determine whether exercise training will attenuate the diabetes-induced deficits in contractile function. METHODS: Female Sprague-Dawley rats (n=33, 257 ± 2 g) were randomly assigned to control (C, 10), diabetic (D, 9), or exercise trained diabetic groups (DET, 14). Diabetes (streptozotocin, 50 mg/kg) was confirmed by urine glucose (>2000 mg/dl). After the onset of diabetes, the DET rats began an 8 wk low intensity treadmill training program. Rats were anesthetized (pentobarbital sodium, 50 mg/kg) and the abdominal surface of the costal diaphragm was exposed. The phrenic nerves were transected and electrodes were placed in the ventral and dorsal costal diaphragm to elicit contractions at 1 and 4 Hz (6V). PiO2 (phosphorescence quenching) and contractile function were measured simultaneously in the medial costal diaphragm. RESULTS: The D group had reduced body (C, 297 ± 9; D, 254 ± 9 g; P≤.05) and diaphragm weight (C, 148 ± 10; D, 113 ± 6 mg; P≤.05). Absolute twitch tension (g) and rate of tension change (dT/dt, g/s) were reduced in D compared to C (P≤0.05). Twitch tension normalized per gram of tissue (N/g) was not different in C and D, while dT/dt (N/g.s) was lower in the D group. Training did not improve body, diaphragm weight, (262 ± 6 g; 131 ± 8 mg) or contractile function. Baseline PiO2 (C, 62 ± 5; D, 61 ± 3; DET, 62 ± 5 mmHg) and mean response time (C, 19 ± 2; D, 16 ± 3; DET, 15 ± 2 s) were similar in the three groups. CONCLUSIONS: The decreases in body and diaphragm weights are characteristic of insulin-dependent diabetes. The D diaphragm produced less absolute tension, and training did not improve contractile function. PiO2 kinetics was similar in all three groups, suggesting that chronic diaphragm activity may be sufficient to maintain the normal QO2 to VO2 balance. (Supported by the Graduate Program Committee, KCOM-ATSU)